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Nucleic Acids as Therapeutic Targets and Agents
Published in David E. Thurston, Ilona Pysz, Chemistry and Pharmacology of Anticancer Drugs, 2021
For long-term knockdown of TERT, retroviral vectors expressing short-hairpin RNAs specific to a segment of the TERT transcript have been used. This RNAi-based technique involves incorporation of the anti-telomerase sequence into the host genome and can provide effective knockdown of TERT. Imetelstat (GRN163L) (see Figure 5.80) is a lipid-conjugated 13-mer oligonucleotide developed by Geron Inc that is complementary to, and binds with high affinity to, the RNA template of telomerase, thereby directly inhibiting telomerase activity. This antisense agent has a proprietary thiophosphoramidate backbone, which provides chemical stability and resistance to the effect of nucleases, thus conferring improved stability in plasma and tissues, as well as significantly improved binding affinity to its target sequence. To improve the ability of imetelstat to permeate through cellular membranes, the oligonucleotide is conjugated to a lipid group. Imetelstat was shown to down-regulate telomerase in Phase I clinical trials and was progressed to Phase 2 clinical trials in Essential Thrombocythemia (ET) in which it showed robust hematologic and molecular responses. In 2019 Geron announced that it would move to a Phase 3 study to evaluate imetelstat in patients with lower-risk myelodysplastic syndromes (MDS) who have relapsed after (or are refractory to) erythroid stimulating agents (ESAs).
Ependymoma in Childhood and Adolescence
Published in David A. Walker, Giorgio Perilongo, Roger E. Taylor, Ian F. Pollack, Brain and Spinal Tumors of Childhood, 2020
Telomerase inhibitor MST-312 has been studied in hTERT-positive, primary ependymoma cell lines (n = 6). Within 72 hours of exposure, this study revealed cellular events suggestive of tumor growth arrest, such as induction of DNA damage, decreased cell proliferation, and decreased cell number. Interestingly, these antitumor effects were readily observed independent of telomere length maintenance. As such, anti-telomerase therapy is a potential candidate for further study in hTERT-positive ependymoma.51 Preliminary work in vitro and in orthotopic xenograft models of the tumor indicates that imetelstat, a telomerase inhibitor, reduced tumor growth and inhibited the activity of tumor-initiating cells.51 In a pediatric phase I study of this agent that enrolled 42 patients with recurrent or refractory brain tumors (including 4 ependymomas), no objective responses were observed. The study closed prematurely, as the regimen proved to be too toxic in the study population.96
Leukemias
Published in Pat Price, Karol Sikora, Treatment of Cancer, 2020
Erythropoiesis-maturing agents (EMAs), which are specific activin fusion proteins that act as ligand traps to neutralize negative regulators of erythropoiesis, have now been tested in patients with LR-MDS. Luspartercept (ACE-536) has shown ability to increase hemoglobin levels in LR-disease and is approved for patients with beta-thalassemia. The Phase II LR-MDS study reveals 63% erythroid responses with 38% achieving red-cell transfusion independence, particularly in patients with ringed sideroblasts or SF3B1-defined LR-MDS. The study met its primary end-points and is anticipated to be approved in 2020.131 Roxadustat (FG-4592) is an oral hypoxia-inducible factor inhibitor being tested in a Phase III study in LD-MDS in an effort to improve anemia.132 Imetelstat, a telomerase inhibitor, is in a Phase II/III study in red-cell transfusion-dependent and ESA-relapsed/refractory LR-MDS patients. Drugs aimed at improving thrombocytopenia, noted in about 50% of all LR-MDS patients, are also being tested. The TPO-receptor agonists romiplostim and elthrombopag have now been tested in Phase III studies and found to have platelet responses associated with survival benefits but are not approved as yet. Several other novel approaches are being tested, including second-generation HMAs, guadecitabine and ASTX727, and combinations of azacytidine with either lenalidomide, vorinostat (a TPO-receptor agonist), or pevonedistat (an NEDD8-activating enzyme).133 Several combination trials of venetoclax with azacytidine, including those adding tagraxofusp, a CD123-targeted drug, in the untreated and relapsed/refractory setting, and studies of immune checkpoint modulation with HMAs are also in progress. Other candidate approaches include vyxeos (CPX-351), a novel liposomal formulation of cytarabine and daunorubicin recently licensed for secondary AML or tMN, targeted IDH1/2 or FLT3 inhibitors, splicesome-modulator H3B-8800, CAR T-cells, and bispecific antibodies.
The pharmacotherapeutic management of patients with myelofibrosis: looking beyond JAK inhibitors
Published in Expert Opinion on Pharmacotherapy, 2023
Andrea Duminuco, Calogero Vetro, Cesarina Giallongo, Giuseppe Alberto Palumbo
Telomerases are enzymes that maintain telomere length by using RNA fragments as a template for telomere elongation, which generally undergoes shortening during normal aging cell division. Telomere maintenance is well-known to be linked to tumorigenesis. Cancer cells can reactivate telomerase activity, allowing them to grow unrestricted and causing cell proliferation [93]. Telomerase expression and activity were reported to increase in approximately 90% of the samples of all cancer cases by Ouellette et al. [94]. Imetelstat binds to telomerase and inhibits their activity, stopping telomerase elongation and apoptosis of malignant cells [94]. Its application as an anticancer agent has been tested on several malignancies, such as non-small-cell lung cancer [95] and transfusion-dependent myelodysplastic syndromes [96]. Concerning MF, in a phase 2 trial for patients relapsed/refractory to JAKi, imetelstat 9.4 mg/kg every three weeks reported a median OS of 30 months versus 20 months for 4.7 mg/kg dose [97], even longer than real-world population (median OS of 12 months) [98]. Imetelstat also showed an improvement in bone marrow grade of fibrosis and activity on the mutant clone with a reduction of mutation variant allele frequency (VAF), usually correlated with better prognosis and prolongation of OS [99,100]. For the trial endpoints, spleen and symptom reduction rates were 10.2% and 32.2%, demonstrating significant clinical benefits with an acceptable safety profile [97].
Advances in myelodysplastic syndromes: promising novel agents and combination strategies
Published in Expert Review of Hematology, 2023
Yazan F. Madanat, Zhuoer Xie, Amer M. Zeidan
Telomere length shortening is noted in patients with MDS due to high telomerase activity [51]. Imetelstat is a first-in-class competitive telomerase inhibitor that targets cells with high telomerase activity and human telomerase reverse transcriptase (hTERT) [52]. The phase 2/3, randomized placebo-controlled trial IMerge (MDS3001, NCT02598661) is currently assessing the use of imetelstat in LR-TD-MDS relapsed/refractory or ineligible for ESA therapy. The phase 2 of the study was reported in 38 patients, and 8-week RBC-TI rate was 42% in the non-del5q cohort with a prolonged median transfusion independence duration of ~20 months [53,54]. On-target effects with reduction in hTERT were also noted, in addition to a reduction in malignant clones using cytogenetic and genomic data [53,55]. The phase 3 trial using imetelstat in LR-MDS has completed accrual and the results are eagerly awaited in 2023.
Myelofibrosis: challenges for preclinical models and emerging therapeutic targets
Published in Expert Opinion on Therapeutic Targets, 2021
In cancer cells, expression of telomerase, an RNA-dependent DNA polymerase which synthesizes tandem repeat DNA sequences called telomeres, is usually required for cell immortalization and long-term tumor growth[66]. Imetelstat, a lipid-conjugated oligonucleotide that targets the RNA template of telomerase, inhibited telomerase activity and cell proliferation in mice models[67]. A pilot study in MF patients with imetelstat induced clinical response and reduction in bone marrow fibrosis but also depleted MF HSC by apoptosis, allowing repopulation of the bone marrow. [68–71] Recent data demonstrated a dose-related, clinically meaningful improvement in symptoms with imetelstat in patients refractory/relapsed to JAK inhibitor and defined 9.4 mg/kg every 21 days as the optimal dosing regimen for the Phase 3 study. Moreover, a subset of patients achieved ≥50% reduction in cytogenetically abnormal clones and significant dose-dependent reductions of mutation burden as well as improvement in overall survival. [72,73]